tbuckley/cabot-search huggingface dataset:
Respiratory syncytial virus infection during infancy and asthma during childhood in the USA (INSPIRE): a population-based, prospective birth cohort study
Authors: Christian Rosas-Salazar, Tatiana Chirkova, Tebeb Gebretsadik, James D Chappell, R Stokes Peebles, William D Dupont, Samadhan J Jadhao, Peter J Gergen, Larry J Anderson, Tina V Hartert
Journal: The Lancet (2023)
The integration of peri-implant soft tissues around zirconia abutments: Challenges and strategies
Authors: Kai Tang, Meng-Lin Luo, Wei Zhou, Li-Na Niu, Ji-Hua Chen, Fu Wang
Journal: Bioactive Materials (2023)

Stable soft tissue integration around the implant abutment attenuates pathogen penetration, protects underlying bone tissue, prevents peri-implantitis and is essential in maintaining long-term implant stability. The desire for "metal free" and "aesthetic restoration" has favored zirconia over titanium abutments, especially for implant restorations in the anterior region and for patients with thin gingival biotype. Soft tissue attachment to the zirconia abutment surface remains a challenge. A comprehensive review of advances in zirconia surface treatment (micro-design) and structural design (macro-design) affecting soft tissue attachment is presented and strategies and research directions are discussed. Soft tissue models for abutment research are described. Guidelines for development of zirconia abutment surfaces that promote soft tissue integration and evidence-based references to inform clinical choice of abutment structure and postoperative maintenance are presented.
Tom Nolan’s research reviews—20 April 2023
Authors: Tom Nolan
Journal: BMJ (2023)

Blood pressure management (tailor's version)Using genetic, biomarker, and other individual characteristics to come up with a tailor-made treatment plan sounds a bit like, well, going to a tailor.When it comes to key decisions about our health, we might well prefer a bespoke outfit (and some will be able to afford one), but, looking at healthcare systems right now, most people are lucky if they can find something that's good enough off the peg.
SAG-RAD: a method for single-cell population genomics of unicellular eukaryotes
Authors: Raphael Gollnisch, Joel Wallenius, Kristin E Gribble, Dag Ahrén, Karin Rengefors
Journal: Molecular Biology and Evolution (2023)

Sequencing of reduced representation libraries enables genotyping of many individuals for population genomic studies. However, high amounts of DNA are required, and the method cannot be applied directly on single cells, preventing its use on most microbes. We developed and implemented the analysis of single amplified genomes followed by restriction-site-associated DNA sequencing to bypass labor-intensive culturing and to avoid culturing bias in population genomic studies of unicellular eukaryotes. This method thus opens the way for addressing important questions about the genetic diversity, gene flow, adaptation, dispersal, and biogeography of hitherto unexplored species.
Leveraging the glymphatic and meningeal lymphatic systems as therapeutic strategies in Alzheimer’s disease: an updated overview of nonpharmacological therapies
Authors: Douglas A. Formolo, Jiasui Yu, Kangguang Lin, Hector W. H. Tsang, Haining Ou, Georg S. Kranz, Suk-Yu Yau
Journal: Molecular Neurodegeneration (2023)

Understanding and treating Alzheimer's disease (AD) has been a remarkable challenge for both scientists and physicians. Although the amyloid-beta and tau protein hypothesis have largely explained the key pathological features of the disease, the mechanisms by which such proteins accumulate and lead to disease progression are still unknown. Such lack of understanding disrupts the development of disease-modifying interventions, leaving a therapeutic gap that remains unsolved. Nonetheless, the recent discoveries of the glymphatic pathway and the meningeal lymphatic system as key components driving central solute clearance revealed another mechanism underlying AD pathogenesis. In this regard, this narrative review integrates the glymphatic and meningeal lymphatic systems as essential components involved in AD pathogenesis. Moreover, it discusses the emerging evidence suggesting that nutritional supplementation, non-invasive brain stimulation, and traditional Chinese medicine can improve the pathophysiology of the disease by increasing glymphatic and/or meningeal lymphatic function. Given that physical exercise is a well-regarded preventive and pro-cognitive intervention for dementia, we summarize the evidence suggesting the glymphatic system as a mediating mechanism of the physical exercise therapeutic effects in AD. Targeting these central solute clearance systems holds the promise of more effective treatment strategies.
pycoMeth: a toolbox for differential methylation testing from Nanopore methylation calls
Authors: Rene Snajder, Adrien Leger, Oliver Stegle, Marc Jan Bonder
Journal: Genome biology (2023)

Abstract We present pycoMeth , a toolbox to store, manage and analyze DNA methylation calls from long-read sequencing data obtained using the Oxford Nanopore Technologies sequencing platform. Building on a novel, rapid-access, read-level and reference-anchored methylation storage format MetH5 , we propose efficient algorithms for haplotype aware, multi-sample consensus segmentation and differential methylation testing. We show that MetH5 is more efficient than existing solutions for storing Oxford Nanopore Technologies methylation calls, and carry out benchmarking for pycoMeth segmentation and differential methylation testing, demonstrating increased performance and sensitivity compared to existing solutions designed for short-read methylation data.
Inferring early genetic progression in cancers with unobtainable premalignant disease
Authors: Ignaty Leshchiner, Edmund A. Mroz, Justin Cha, Daniel Rosebrock, Oliver Spiro, Juliana Bonilla-Velez, William C. Faquin, Armida Lefranc-Torres, Derrick T. Lin, William A. Michaud, Gad Getz, James W. Rocco
Journal: Nature Cancer (2023)

Abstract Analysis of premalignant tissue has identified the typical order of somatic events leading to invasive tumors in several cancer types. For other cancers, premalignant tissue is unobtainable, leaving genetic progression unknown. Here, we demonstrate how to infer progression from exome sequencing of primary tumors. Our computational method, PhylogicNDT, recapitulated the previous experimentally determined genetic progression of human papillomavirus-negative (HPV – ) head and neck squamous cell carcinoma (HNSCC). We then evaluated HPV + HNSCC, which lacks premalignant tissue, and uncovered its previously unknown progression, identifying early drivers. We converted relative timing estimates of driver mutations and HPV integration to years before diagnosis based on a clock-like mutational signature. We associated the timing of transitions to aneuploidy with increased intratumor genetic heterogeneity and shorter overall survival. Our approach can establish previously unknown early genetic progression of cancers with unobtainable premalignant tissue, supporting development of experimental models and methods for early detection, interception and prognostication.
Nationwide health, socio-economic and genetic predictors of COVID-19 vaccination status in Finland
Authors: Tuomo Hartonen, Bradley Jermy, Hanna Sõnajalg, Pekka Vartiainen, Kristi Krebs, Andrius Vabalas, Andres Metspalu, Tõnu Esko, Mari Nelis, Georgi Hudjashov, Tuija Leino, Hanna Nohynek, Jonas Sivelä, Reedik Mägi, Mark Daly, Hanna M. Ollila, Lili Milani, Markus Perola, Samuli Ripatti, Andrea Ganna
Journal: Nature Human Behaviour (2023)

Abstract Understanding factors associated with COVID-19 vaccination can highlight issues in public health systems. Using machine learning, we considered the effects of 2,890 health, socio-economic and demographic factors in the entire Finnish population aged 30–80 and genome-wide information from 273,765 individuals. The strongest predictors of vaccination status were labour income and medication purchase history. Mental health conditions and having unvaccinated first-degree relatives were associated with reduced vaccination. A prediction model combining all predictors achieved good discrimination (area under the receiver operating characteristic curve, 0.801; 95% confidence interval, 0.799–0.803). The 1% of individuals with the highest predicted risk of not vaccinating had an observed vaccination rate of 18.8%, compared with 90.3% in the study population. We identified eight genetic loci associated with vaccination uptake and derived a polygenic score, which was a weak predictor in an independent subset. Our results suggest that individuals at higher risk of suffering the worst consequences of COVID-19 are also less likely to vaccinate.
satmut_utils: a simulation and variant calling package for multiplexed assays of variant effect
Authors: Ian Hoskins, Song Sun, Atina Cote, Frederick P. Roth, Can Cenik
Journal: Genome biology (2023)

Abstract The impact of millions of individual genetic variants on molecular phenotypes in coding sequences remains unknown. Multiplexed assays of variant effect (MAVEs) are scalable methods to annotate relevant variants, but existing software lacks standardization, requires cumbersome configuration, and does not scale to large targets. We present satmut_utils as a flexible solution for simulation and variant quantification. We then benchmark MAVE software using simulated and real MAVE data. We finally determine mRNA abundance for thousands of cystathionine beta-synthase variants using two experimental methods. The satmut_utils package enables high-performance analysis of MAVEs and reveals the capability of variants to alter mRNA abundance.
Carriers of the p.P522R variant in PLCγ2 have a slightly more responsive immune system
Authors: Annieck M. Diks, Cristina Teodosio, Bas de Mooij, Rick J. Groenland, Brigitta A. E. Naber, Inge F. de Laat, Sandra A. Vloemans, Susan Rohde, Marien I. de Jonge, Linda Lorenz, Debbie Horsten, Jacques J. M. van Dongen, Magdalena A. Berkowska, Henne Holstege
Journal: Molecular Neurodegeneration (2023)

Abstract Background The rs72824905 single-nucleotide polymorphism in the PLCG2 gene, encoding the p.P522R residue change in Phospholipase C gamma 2 (PLCγ2), associates with protection against several dementia subtypes and with increased likelihood of longevity. Cell lines and animal models indicated that p.P522R is a functional hypermorph. We aimed to confirm this in human circulating peripheral immune cells. Methods We compared effects of p.P522R on immune system function between carriers and non-carriers (aged 59-103y), using in-depth immunophenotyping, functional B-cell and myeloid cell assays, and in vivo SARS-CoV-2 vaccination. Results In line with expectations, p.P522R impacts immune cell function only slightly, but it does so across a wide array of immune cell types. Upon B-cell stimulation, we observed increased PLCγ2 phosphorylation and calcium release, suggesting increased B-cell sensitivity upon antigen recognition. Further, p.P522R-carriers had higher numbers of CD20++CD21-CD24+ naive B cells and IgG1+ memory B cells. In myeloid cells, normalized ROS production was higher upon PLCγ2-dependent stimulation. On classical monocytes, CD33 levels were elevated. Furthermore, carriers expressed lower levels of allergy-related FcεRI on several immune cell subsets. Nevertheless, carriers and non-carriers had similar serological responses to SARS-CoV-2 vaccination. Conclusion The immune system from p.P522R-carriers is slightly more responsive to stimulation than in non-carriers.
Artificial intelligence based polyp size measurement in gastrointestinal endoscopy using the auxiliary water jet as a reference
Authors: Boban Sudarevic, Philipp Sodmann, Ioannis Kafetzis, Joel Troya, Thomas J. Lux, Zita Saßmannshausen, Katja Herlod, Stefan A. Schmidt, Markus Brand, Katrin Schöttker, Wolfram G. Zoller, Alexander Meining, Alexander Hann
Journal: Endoscopy (2023)

Measurement of colorectal polyp size during endoscopy is mainly performed visually. In this work, we propose a novel polyp size measurement system (Poseidon) based on artificial intelligence (AI) using the auxiliary waterjet as a measurement reference.Visual estimation, biopsy forceps-based estimation, and Poseidon were compared using a computed tomography colonography-based silicone model with 28 polyps of defined sizes. Four experienced gastroenterologists estimated polyp sizes visually and with biopsy forceps. Furthermore, the gastroenterologists recorded images of each polyp with the waterjet in proximity for the application of Poseidon. Additionally, Poseidon's measurements of 29 colorectal polyps during routine clinical practice were compared with visual estimates.In the silicone model, visual estimation had the largest median percentage error of 25.1 % (95 %CI 19.1 %-30.4 %), followed by biopsy forceps-based estimation: median 20.0 % (95 %CI 14.4 %-25.6 %). Poseidon gave a significantly lower median percentage error of 7.4 % (95 %CI 5.0 %-9.4 %) compared with other methods. During routine colonoscopies, Poseidon presented a significantly lower median percentage error (7.7 %, 95 %CI 6.1 %-9.3 %) than visual estimation (22.1 %, 95 %CI 15.1 %-26.9 %).In this work, we present a novel AI-based method for measuring colorectal polyp size with significantly higher accuracy than other common sizing methods.
3D-printed scaffolds with 2D hetero-nanostructures and immunomodulatory cytokines provide pro-healing microenvironment for enhanced bone regeneration
Authors: Xifeng Liu, Bipin Gaihre, Sungjo Park, Linli Li, Babak Dashtdar, Maria D. Astudillo Potes, Andre Terzic, Benjamin D. Elder, Lichun Lu
Journal: Bioactive Materials (2023)

Three-dimensional (3D) printing technology is driving forward the progresses of various engineering fields, including tissue engineering. However, the pristine 3D-printed scaffolds usually lack robust functions in stimulating desired activity for varied regeneration applications. In this study, we combined the two-dimensional (2D) hetero-nanostructures and immuno-regulative interleukin-4 (IL-4) cytokines for the functionalization of 3D-printed scaffolds to achieve a pro-healing immuno-microenvironment for optimized bone injury repair. The 2D hetero-nanostructure consists of graphene oxide (GO) layers, for improved cell adhesion, and black phosphorous (BP) nanosheets, for the continuous release of phosphate ions to stimulate cell growth and osteogenesis. In addition, the 2D hetero-nanolayers facilitated the adsorption of large content of immuno-regulative IL-4 cytokines, which modulated the polarization of macrophages into M2 phenotype. After in vivo implantation in rat, the immuno-functioned 3D-scaffolds achieved in vivo osteo-immunomodulation by building a pro-healing immunological microenvironment for better angiogenesis and osteogenesis in the defect area and thus facilitated bone regeneration. These results demonstrated that the immuno-functionalization of 3D-scaffolds with 2D hetero-nanostructures with secondary loading of immuno-regulative cytokines is an encouraging strategy for improving bone regeneration.
The Majority of Chronic Myeloid Leukaemia Patients Who Cease Imatinib after Achieving a Sustained Complete Molecular Response (CMR) Remain in CMR, and Any Relapses Occur Early.
Authors: Davi D M Ross, Andrew Grigg, Anthony Schwarer, Christopher Arthur, Kerryn Loftus, Anthony K Mills, Robin Filshie, Ruth Columbus, John Reynolds, John F Seymour, Susan Branford, Timothy Hughes
Journal: Blood (2008)
Tumor and immune remodeling following radiotherapy in human renal cell carcinoma
Authors: Jacky Chow, Adil Khan, Madeline Gaudieri, Brianna J Wasik, Alexis Conway, Kah Teong Soh, Elizabeth A Repasky, Thomas Schwaab, Paul K Wallace, Scott I Abrams, Anurag K Singh, Jason B Muhitch
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Studies evaluating peripheral patient samples show radiation can modulate immune responses, yet the biological changes in human tumors particularly at the cellular level remain largely unknown. Here, we address how radiation treatment shapes the immune compartment and interactions with cancer cells within renal cell carcinoma (RCC) patient tumors. Methods To identify how radiation shaped the immune compartment and potential immune interactions with tumor cells we evaluated RCC tumors from patients treated only with nephrectomy or with radiation followed by nephrectomy. Spectral flow cytometry using a 35-marker panel was performed on cell suspensions to evaluate protein expression within immune subsets. To reveal how radiation alters programming of immune populations and interactions with tumor cells, we examined transcriptional changes by single-cell RNA sequencing (scRNAseq). Results Spectral flow cytometry analysis revealed increased levels of early-activated as well as effector programmed cell death protein-1 (PD-1) + CD8 T-cell subsets within irradiated tumors. Following quality control, scRNAseq of tumor samples from nephrectomy-only or radiation followed by nephrectomy-treated patients generated an atlas containing 34,626 total cells. Transcriptional analysis revealed increased transition from stem-like T-cell populations to effector T cells in irradiated tumors. Interferon (IFN) pathways, that are central to radiation-induced immunogenicity, were enriched in irradiated lymphoid, myeloid, and cancer cell populations. Focused cancer cell analysis showed enhanced antigen presentation and increased predicted TRAIL-mediated and IFN-mediated interactions between tumor cells and the same effector T-cell subsets increased by radiation. TRAIL and IFN pathways enriched in irradiated tumors were associated with survival in patients treated with immunotherapy. Conclusions These findings identify the source of IFN enrichment within irradiated RCC and reveal heightened levels of PD-1 + CD8 + T-cell subsets and increased probability of interactions with tumor cells following standalone radiation treatment. This study provides a window into the irradiated tumor-immune microenvironment of patients and rationale for treatment combinations.
Identification of Adult Patients With Classical Dyskeratosis Congenita or Cryptic Telomere Biology Disorder by Telomere Length Screening Using Age-modified Criteria
Authors: Mareike Tometten, Martin Kirschner, Robert Meyer, Matthias Begemann, Insa Halfmeyer, Margherita Vieri, Kim Kricheldorf, Angela Maurer, Uwe Platzbecker, Markus Radsak, Philippe Schafhausen, Selim Corbacioglu, Britta Höchsmann, C. Matthias Wilk, Claas Hinze, Jörg Chromik, Michael Heuser, Michael Kreuter, Steffen Koschmieder, Jens Panse, Susanne Isfort, Ingo Kurth, Tim H. Brümmendorf, Fabian Beier
Journal: HemaSphere (2023)

Telomere biology disorders (TBD) result from premature telomere shortening due to pathogenic germline variants in telomere maintenance-associated genes. In adults, TBD are characterized by mono/oligosymptomatic clinical manifestations (cryptic TBD) contributing to severe underdiagnosis. We present a prospective multi-institutional cohort study where telomere length (TL) screening was performed in either newly diagnosed patients with aplastic anemia (AA) or if TBD was clinically suspected by the treating physician. TL of 262 samples was measured via flow-fluorescence in situ hybridization (FISH). TL was considered suspicious once below the 10th percentile of normal individuals (standard screening) or if below 6.5 kb in patients >40 years (extended screening). In cases with shortened TL, next generation sequencing (NGS) for TBD-associated genes was performed. The patients referred fell into 6 different screening categories: (1) AA/paroxysmal nocturnal hemoglobinuria, (2) unexplained cytopenia, (3) dyskeratosis congenita, (4) myelodysplastic syndrome/acute myeloid leukemia, (5) interstitial lung disease, and (6) others. Overall, TL was found to be shortened in 120 patients (n = 86 standard and n = 34 extended screening). In 17 of the 76 (22.4%) standard patients with sufficient material for NGS, a pathogenic/likely pathogenic TBD-associated gene variant was identified. Variants of uncertain significance were detected in 17 of 76 (22.4%) standard and 6 of 29 (20.7%) extended screened patients. Expectedly, mutations were mainly found in TERT and TERC. In conclusion, TL measured by flow-FISH represents a powerful functional in vivo screening for an underlying TBD and should be performed in every newly diagnosed patient with AA as well as other patients with clinical suspicion for an underlying TBD in both children and adults.
Ex vivo drug response heterogeneity reveals personalized therapeutic strategies for patients with multiple myeloma
Authors: Klara Kropivsek, Paul Kachel, Sandra Goetze, Rebekka Wegmann, Yasmin Festl, Yannik Severin, Benjamin D. Hale, Julien Mena, Audrey van Drogen, Nadja Dietliker, Joëlle Tchinda, Bernd Wollscheid, Markus G. Manz, Berend Snijder
Journal: Nature Cancer (2023)

Abstract Multiple myeloma (MM) is a plasma cell malignancy defined by complex genetics and extensive patient heterogeneity. Despite a growing arsenal of approved therapies, MM remains incurable and in need of guidelines to identify effective personalized treatments. Here, we survey the ex vivo drug and immunotherapy sensitivities across 101 bone marrow samples from 70 patients with MM using multiplexed immunofluorescence, automated microscopy and deep-learning-based single-cell phenotyping. Combined with sample-matched genetics, proteotyping and cytokine profiling, we map the molecular regulatory network of drug sensitivity, implicating the DNA repair pathway and EYA3 expression in proteasome inhibitor sensitivity and major histocompatibility complex class II expression in the response to elotuzumab. Globally, ex vivo drug sensitivity associated with bone marrow microenvironmental signatures reflecting treatment stage, clonality and inflammation. Furthermore, ex vivo drug sensitivity significantly stratified clinical treatment responses, including to immunotherapy. Taken together, our study provides molecular and actionable insights into diverse treatment strategies for patients with MM.
CD103+ regulatory T cells underlie resistance to radio-immunotherapy and impair CD8+ T cell activation in glioblastoma
Authors: Luuk van Hooren, Shanna M. Handgraaf, Daan J. Kloosterman, Elham Karimi, Lotte W.H.G. van Mil, Awa A. Gassama, Beatriz Gomez Solsona, Marnix H. P. de Groot, Dieta Brandsma, Daniela F. Quail, Logan A. Walsh, Gerben R. Borst, Leila Akkari
Journal: Nature Cancer (2023)

Glioblastomas are aggressive primary brain tumors with an inherent resistance to T cell-centric immunotherapy due to their low mutational burden and immunosuppressive tumor microenvironment. Here we report that fractionated radiotherapy of preclinical glioblastoma models induce a tenfold increase in T cell content. Orthogonally, spatial imaging mass cytometry shows T cell enrichment in human recurrent tumors compared with matched primary glioblastoma. In glioblastoma-bearing mice, α-PD-1 treatment applied at the peak of T cell infiltration post-radiotherapy results in a modest survival benefit compared with concurrent α-PD-1 administration. Following α-PD-1 therapy, CD103+ regulatory T cells (Tregs) with upregulated lipid metabolism accumulate in the tumor microenvironment, and restrain immune checkpoint blockade response by repressing CD8+ T cell activation. Treg targeting elicits tertiary lymphoid structure formation, enhances CD4+ and CD8+ T cell frequency and function and unleashes radio-immunotherapeutic efficacy. These results support the rational design of therapeutic regimens limiting the induction of immunosuppressive feedback pathways in the context of T cell immunotherapy in glioblastoma.